Modular Synthesis Research Articles

Modular Total Synthesis and Antimycobacterial Activity of Rufomycins.

The rufomycins are a family of nonribosomal cyclic peptides isolated from the deep sea-dwelling Streptomyces atratus. Herein, we describe the total synthesis of six congeners in the rufomycin family. Synthesis was achieved through a modular solid-phase strategy, incorporating synthetic nonproteinogenic amino acids: l-2-amino-4-hexenoic acid, tert-prenyl-l-tryptophan (and related (S)-epoxide), and N-methyl-δ-hydroxy-l-leucine. Following macrolactamization, these peptides were further diversified through late-stage oxidation and secondary cyclization to furnish a library of six synthetic natural products. Rufomycins 4 and 22, bearing an unusual 6-hydroxypiperidin-2-one structural motif, exhibited impressive activity against the virulent H37Rv strain of Mycobacterium tuberculosis (MIC50 = 350-670 nM).

Highly Regioselective Modular Assembly of 3-Phosphonyl Polysubstituted Pyridines through Radical Cascade Cyclization of 1,5-Enynes with Phosphine Oxide by Photoinitiation.

A series of 3-phosphonyl polysubstituted pyridine were first synthesized by photocatalysis, combining a phosphonyl radical cascade reaction, Boc deprotection, and aromatization. This strategy can avoid the difficulties of activating the C3-H bond on pyridine to synthesize 3-phosphonylpyridine under mild conditions. Furthermore, by constructing different enynes, we can achieve the metal-free modular synthesis of 3-phosphonyl polysubstituted pyridine, which will be transferred into a new type of phosphine ligand. This is of significance for organometallic catalysis. The regioselective control and detailed reaction mechanism of the cascade reaction are explained by DFT calculations.

Engineering a Silk Protein-Mediated Customizable Compartment for Modular Metabolic Synthesis.

Microbial cell factories provide a nontoxic, economical way for the synthesis of various chemicals and drugs, garnering significant attention from researchers. However, excessive dispersion of enzymes and accumulation of intermediate metabolites in the production process will weaken the reaction efficiency of the pathway enzyme. In this study, a cellular compartment was constructed to isolate the enzyme reaction space and optimize the modular metabolic synthesis. First, a special spider silk protein was designed and constructed to form protein condensates in microbial cells, and its synthetic microcompartment effects were investigated. Second, the interaction of short peptide pairs or direct fusion based on the silk protein was used to recruit a variety of enzymes to improve the efficiency of enzyme catalysis. Third, the 2'-fucosyllactose (2'-FL) de novo synthesis pathway and its modular optimization were carried out to verify the mode. Finally, a synthetic compartment was introduced into the pathway to directly aggregate the 2'-FL synthesis pathway, thus obtaining synthetic-compartment-mediated multienzyme aggregates. The experimental results showed that the titer of 2'-FL was significantly improved compared with those of wild-type and modular-optimized free enzymes. The utilization of this cell microcompartment offers a novel avenue for the aggregation of diverse enzymes, thereby offering an innovative approach for enhancing the efficiency of the microbial modular metabolic pathway.

Modular Synthesis of Dehydroprolines by an Energy‐Transfer Enabled Cloke‐Wilson Rearrangement

AbstractA one‐pot photocatalytic method is reported for the generation of dehydroprolines, valuable precursors to 5‐aryl prolines. Imines, obtained via simple condensation of aminocyclopropane carboxylates (ACPC) with a broad range of aldehydes, were employed in this transformation without purification. We demonstrate this energy‐transfer (EnT) enabled Cloke‐Wilson‐type rearrangement affords both the rare 1,2‐dehydroprolines or the more thermodynamically favored 1,5‐isomers with up to >20 : 1 selectivity in both directions, using an identical catalytic system from the same starting material. Syntheses of intermediates of bioactive molecules in high yields and selectivity highlight this enabling transformation. Mechanistic studies support the proposed triplet‐triplet EnT mode of activation, distinct from the previously developed singlet excited states accessed via UV excitation.

Modular Synthesis of Dehydroprolines by an Energy-Transfer Enabled Cloke-Wilson Rearrangement.

A one-pot photocatalytic method is reported for the generation of dehydroprolines, valuable precursors to 5-aryl prolines. Imines, obtained via simple condensation of aminocyclopropane carboxylates (ACPC) with a broad range of aldehydes, were employed in this transformation without purification. We demonstrate this energy-transfer (EnT) enabled Cloke-Wilson-type rearrangement affords both the rare 1,2-dehydroprolines or the more thermodynamically favored 1,5-isomers with up to >20 : 1 selectivity in both directions, using an identical catalytic system from the same starting material. Syntheses of intermediates of bioactive molecules in high yields and selectivity highlight this enabling transformation. Mechanistic studies support the proposed triplet-triplet EnT mode of activation, distinct from the previously developed singlet excited states accessed via UV excitation.

From Molecular to Polymeric Donors: Prolonged Charge Separation in Modular Photoredox-Active Ru(II) Polypyridyl-Type Triads.

In this contribution, the divergent modular synthesis of photoredox-active dyads, triads and a tetrad descending from one ligand precursor is presented by combining "chemistry-on-the-ligand", stepwise complexation and "chemistry-on-the-complex" with minimal synthetic efforts. In the final step, Pd-mediated borylation and subsequent Suzuki-Miyaura cross-coupling was employed to introduce the different (multi)donor moieties at the preassembled P-A dyad subunit. The (spectro-)electrochemical data revealed preserved redox properties of the subunits and minimal driving force for oxidative quenching by the naphthalene diimide-based (NDI) acceptor and, thus, high-energy charge separated (CS) states. Time-resolved transient absorption and emission data revealed the formation of long-lived CS states in the polymer-based triads, i.e., the CS lifetime is extended by 2 orders of magnitude in comparison to the molecular triad. The long-lived CS state (13.2 μs) of the conjugated polycarbazole (Carbn) multidonor demonstrates that the rational modular design and efficient synthesis of advanced photoredox-active assemblies can be readily achieved by late-stage diversification utilizing the "chemistry-on-the-complex" approach.

Modular Synthesis of Geminal Iododiboron Compounds via Alkylation of Chlorodiborylmethane.

α-Halogenated geminal bis(boronates) are emerging as multifunctional building blocks for organic synthesis. Currently, their synthetic utilization is still restricted due to a lack of efficient preparation methods. Herein, we report a direct, modular synthesis of gem-iododiborylalkanes using alkyl halides and a lithiated chlorodiborylmethane reagent. Compared with previously reported methods, this protocol features modular assembly, high efficiency, and good tolerance to various functional groups.

Stabilized Carbon Radical-Mediated Assembly of Arylthianthrenium Salts, Alkenes and Amino Acid/Peptide Derivatives.

Efficiently assembling amino acids and peptides with bioactive molecules facilitates the modular and streamlined synthesis of a diverse library of peptide-related compounds. Particularly notable is their application in pharmaceutical development, leveraging site-selective late-stage functionalization. Here, a visible light-induced three-component reaction involving arylthianthrenium salts, amino acid/peptide derivatives, and alkenes are introduced. This approach utilizes captodatively-stabilized carbon radicals to enable radical-radical C─C coupling, effectively constructing complex bioactive molecules. This method offers a promising alternative route for modular synthesis of peptide-derived bio-relevant compounds.

Emergence of Low-Cost and High-Performance Nonfused Ring Electron Acceptors.

ConspectusOrganic solar cells (OSCs) have garnered significant attention in academic and industrial circles due to their advantages such as lightweight, excellent bending performance, and the ability to be fabricated into semitransparent devices. Since the proposal of the bulk heterojunction concept by Heeger et al. in 1995, conjugated polymer/fullerene pairs have gradually emerged as the optimal choice for active layer materials in OSCs. Fullerene derivatives were preferred as electron acceptors in OSCs because of their high electron mobility. However, due to limitations such as insufficient light absorption, limited derivative potential, and poor energy level tunability, the power conversion efficiency (PCE) of OSCs based on fullerene derivatives has encountered a bottleneck of approximately 12%, despite the continuous updates in polymer donor materials over nearly two decades of development, leading to a gradual decline in their importance. By contrast, nonfullerene electron acceptors (NFAs) have gradually gained dominance in this field since first appearing in 2015, thanks to their advantages of tunable absorption spectrum, adjustable energy levels, and modifiable chemical structure. Among nonfullerene acceptors, fused-ring electron acceptors (FREAs) such as ITIC and Y6 have achieved significant progress, boosting the PCE of OSCs to 20%. This milestone achievement indicates the potential of their commercial applications. However, the synthesis process of FREA is complex and often constrained by low-yield ring-closure reactions, resulting in high costs.The molecular backbone of nonfused ring electron acceptors (NFREAs) is composed of single bonds, which enables the adoption of modular synthesis mainly via Stille (based on organotin reactant) and/or Suzuki (based on organoboron reactant) coupling or C-H activation (without prefunctionalization) and avoids low-yield ring-closing reactions, thus making them a potential alternative to fused-ring acceptors. To achieve a planar molecular backbone and minimize energy loss due to conformational rotation, our team innovatively used intramolecular noncovalent interactions as a replacement for traditional covalent bonds. Furthermore, to address the issues of poor solubility and excessive aggregation during film formation for NFREAs, we strategically introduced sterically hindered side groups, such as 2,6-bis(alkyloxy)phenyl and diphenylamino, into the molecular design, effectively mitigating these problems. These innovative design concepts have significantly advanced the development of high-performance NFREAs and have garnered increasing attention from the research community. The PCEs of OSCs based on NFREAs have significantly improved from less than 10% to close to 20% since their initial discovery. By optimizing the device fabrication process, we have achieved a PCE of over 19%, which is comparable to that of FREAs. This article will delve into the evolution and latest research progress of NFREAs, aiming to provide valuable insights and guidance for the design of cost-effective and high-performance NFREA materials.

A Unified Phosphoramidite Platform for the Synthesis of Morpholino Oligonucleotides and Diverse Chimeric Backbones.

Phosphorodiamidate Morpholino Oligonucleotides (PMOs) have been well established in the milieu of FDA-approved oligonucleotide-based drugs in the past decade. Given their relevance in antisense therapeutics, a DNA/RNA synthesizer-compatible modular synthesis protocol of PMOs is long awaited to explore next-generation PMO chimeras with other therapeutically proven oligonucleotide backbones. Herein, we demonstrate a streamlined 5' → 3'phosphoramidite approach for the synthesis of PMOs using tert-butyl-protected 5'-tBu-morpholino phosphoramidites, which were synthesized from 5'-OH morpholino monomers derived from commercially available ribonucleosides. 2-Cyanoethyl (CE)-protected 5'-CE-morpholino phosphoramidites were also synthesized to generate thiophosphoramidate (TMO) and phosphoramidate (MO) morpholino oligonucleotides. Full-length PMOs and TMOs in exceptional overall yields were obtained with operational simplicity and compatibility with automated DNA/RNA synthesizers utilizing controlled pore glass (CPG) as the solid support and CH3CN as the solvent. Importantly, this method has opened the possibility of designing various biologically relevant ASO design modalities, such as PMO-TMO and PMO-MO, which were inaccessible otherwise. Moreover, DNA nucleotides were also incorporated to generate PMO-psDNA and PMO-DNA using commercially available 5'-DNA phosphoramidites. The biophysical properties of all synthesized oligonucleotides were analyzed using UV melting and circular dichroism studies. The serum interaction profile and innate immune response of the PS-modified polythymidine oligonucleotides were analyzed and it was found that the mixed backbone oligonucleotides had a balanced profile compared to fully charged or neutral extremities. Overall, the synthesis is amenable to fast generation of various types of PMO chimeras for biological screening, which will expedite their therapeutic exploration and transition to clinic.

Comprehensive Modular Synthesis of Ganglioside Glycans and Evaluation of their Binding Affinities to Siglec‐7 and Siglec‐9

AbstractIn the present work, bacterial glycosyltransferases are utilized to construct ganglioside glycans in a convergent approach via a sugar‒nucleotide regeneration system and one‐pot multienzyme reactions. Starting from β‐lactoside enables the diversification of both the glycan moieties and the linkages in the lower α‐arm and upper β‐arm. Overall, a comprehensive panel of 24 natural a‐series (GM3, GM2, GM1a, GD1a, GT1a, and fucosyl‐GM1), b‐series (GD3, GD2, GD1b, GT1b, and GQ1b), c‐series (GT3, GT2, GT1c, GQ1c, and GP1c), α‐series (GM1α, GD1aα, and GT1aα), and o‐series (GA2, GA1, GM1b, GalNAc‐GM1b, and GD1c) ganglioside glycans are prepared, which are suitable for biological studies and further applications. Moreover, a microarray is constructed with these synthesized ganglioside glycans to investigate their binding specificity with recombinant Fc‐fused Siglec‐7 and Siglec‐9, which are immune checkpoint‐like glycan recognition proteins on natural killer cells. The microarray binding results reveal that GD3 and GT1aα are specific ligands for Siglec‐7 and Siglec‐9, respectively, and this discovery can lead to the identification of appropriate ligands for investigating the roles of these Siglecs in immunomodulation.

Metallaphotocatalytic triple couplings for modular synthesis of elaborate N-trifluoroalkyl anilines

The integration of trifluoromethyl groups and three-dimensional quaternary carbon moieties into organic molecules has emerged as a prominent strategy in medicinal chemistry to augment drug efficacy. Although trifluoromethyl (hetero)aromatic amines and derivatives are prevalent frameworks in pharmaceuticals, the development of trifluoromethyl-embedded, intricately structured alkyl amine scaffolds for medicinal research remains a significant challenge. Herein, we present a metallaphotoredox multicomponent amination strategy employing 3,3,3-trifluoropropene, nitroarenes, tertiary alkylamines, and carboxylic acids. This synthetic pathway offers notable advantages, including the accessibility and cost-effectiveness of starting materials, high levels of chemo- and regioselectivity, and modularity. Furthermore, this approach enables the synthesis of a broad spectrum of aniline compounds featuring both trifluoromethyl group and distal quaternary carbon motifs along the aliphatic chains. The accelerated access to such elaborate N-trifluoroalkyl anilines likely involves three sequential radical-mediated coupling events, providing insightful implications for the retrosynthesis of potential compounds in organic synthesis and drug discovery.

Facile Access to Phosphorus Ylide-fused Heteroarenes Possessing Tunable Optoelectronic Properties and High Nonlinear Optical Performances.

We report here a novel family of ylidic P-heteroarenes (P1-P6), structurally featuring unique phosphonium cyclopentadienylide (P-Cp)-fused π-skeletons and synthetically prepared via an unexpected one-pot [2+3]/[3+3] phospha-annulation reaction. While the facile and modular synthesis allows the fine-tuning of their optical absorptions and redox properties, single-crystallographic and theoretical analysis of these P-heteroarenes further reveal that the fusion of P-Cp moiety leads to substantial intramolecular charge-separated features with high ylidic character values of up to 84 %. Benefitted from such dipolar structures, these P-heteroarenes not only allows stepwise electrophilic substitution reaction for further structural π-expansions, but also exhibit excellent nonlinear optical (NLO) responses and optical limiting (OL) performances comparable to or exceed those of C60. As a model compound, the persistent radical-anion salt of P5a was also prepared through chemical reduction, thus offering valuable insights into the electronic structures of reduced P-ylidic species. Our work not only established a highly efficient synthetic method toward new P-heteroarenes, but also provide fundamental understanding of those fused-ring ylidic P-heterocycles with promising NLO/OL applications.

Facile Access to Phosphorus Ylide‐fused Heteroarenes Possessing Tunable Optoelectronic Properties and High Nonlinear Optical Performances

AbstractWe report here a novel family of ylidic P‐heteroarenes (P1–P6), structurally featuring unique phosphonium cyclopentadienylide (P−Cp)‐fused π‐skeletons and synthetically prepared via an unexpected one‐pot [2+3]/[3+3] phospha‐annulation reaction. While the facile and modular synthesis allows the fine‐tuning of their optical absorptions and redox properties, single‐crystallographic and theoretical analysis of these P‐heteroarenes further reveal that the fusion of P−Cp moiety leads to substantial intramolecular charge‐separated features with high ylidic character values of up to 84 %. Benefitted from such dipolar structures, these P‐heteroarenes not only allows stepwise electrophilic substitution reaction for further structural π‐expansions, but also exhibit excellent nonlinear optical (NLO) responses and optical limiting (OL) performances comparable to or exceed those of C60. As a model compound, the persistent radical‐anion salt of P5a was also prepared through chemical reduction, thus offering valuable insights into the electronic structures of reduced P‐ylidic species. Our work not only established a highly efficient synthetic method toward new P‐heteroarenes, but also provide fundamental understanding of those fused‐ring ylidic P‐heterocycles with promising NLO/OL applications.

Synthesis and Application of a Versatile Immunoproteasome Activity Probe.

The immunoproteasome (iCP) has gained significant interest in recent years as it has been discovered to be significantly expressed under inflammatory conditions, as well as playing significant roles in several diseases, such as autoimmune disorders, viral infection, and cancer. Selective inhibitors have been generated as a method to overcome the off-target effects of current proteasome inhibitor therapeutics. However, selective probes that allow for monitoring this protein complex remain limited, hindering our understanding of the iCP. Current probes are non-selective, not commercially available, or require difficult synthesis. Here, we describe the modular synthesis and application of an iCP-selective probe. The modular nature of the synthetic strategy can enable the incorporation of different fluorophores and covalent warheads, demonstrating the versatility of this probe.

Adaptive Synthesis, Supramolecular Behavior, and Biological Properties of Amphiphilic Carbosilane-Phosphonium Dendrons with Tunable Structure.

Here, we present a modular synthesis as well as physicochemical and biological evaluation of a new series of amphiphilic dendrons carrying triphenylphosphonium groups at their periphery. Within the series, the size and mutual balance of lipophilic and hydrophilic domains are systematically varied, changing the dendron shape from cylindrical to conical. In physiological solution, the dendrons exhibit very low critical micelle concentrations (2.6-4.9 μM) and form stable and uniform micelles 6-12 nm in diameter, depending on dendron shape; the results correlate well with molecular dynamics simulations. The compounds show relatively high cytotoxicity (IC50 1.2-21.0 μM) associated with micelle formation and inversely related to the size of assembled particles. Depending on their shape, the dendrons show promising results in terms of dendriplex formation and antibacterial activity. In addition to simple amphiphilic dendrons, a fluorescently labeled analogue was also prepared and utilized as an additive visualizing the dendron's cellular uptake.

Diastereoselective Double Annulation of Allenoates with Povarov Adducts: Modular Synthesis of Multisubstituted Pyrroloquinolines.

Herein, we report an atom-economical, one-pot, four-component, diastereoselective double-annulation reaction to construct polyfused pyrroloquinolines. This reaction highlights the cyclization of in situ-formed Povarov adducts with allenoates for the first time.

Complexity‐Building Exhaustive Dearomatization of Benzenoid Aromatics within an ESIPT‐Initiated Three‐Step Photochemical Cascade.

AbstractDearomative cycloadditions offer rapid access to complex 3D molecular architectures, commonly via a sp2‐to‐sp3 rehybridization of two atoms of an aromatic ring. Here we report that the 6e π‐system of a benzenoid aromatic pendant could be exhaustively depleted within a single photochemical cascade. An implementation of this approach involves the initial dearomative [4+2] cycloaddition of the Excited State Intramolecular Proton Transfer (ESIPT)‐generated azaxylylene, followed by two consecutive [2+2] cycloadditions of auxiliary π moieties strategically positioned in the photoprecursor. Such photochemical cascade fully dearomatizes the benzenoid aromatic ring, saturating all six sp2 atoms to yield a complex sp3‐rich scaffold with high control of its 3D molecular shape, rendering it a robust platform for rapid systematic mapping of underexplored chemical space. Significant growth of molecular complexity—starting with a modular synthesis of photoprecursors from readily available building blocks—is quantified by Böttcher score calculations.

Complexity-Building Exhaustive Dearomatization of Benzenoid Aromatics within an ESIPT-Initiated Three-Step Photochemical Cascade.

Dearomative cycloadditions offer rapid access to complex 3D molecular architectures, commonly via a sp2-to-sp3 rehybridization of two atoms of an aromatic ring. Here we report that the 6e π-system of a benzenoid aromatic pendant could be exhaustively depleted within a single photochemical cascade. An implementation of this approach involves the initial dearomative [4+2] cycloaddition of the Excited State Intramolecular Proton Transfer (ESIPT)-generated azaxylylene, followed by two consecutive [2+2] cycloadditions of auxiliary π moieties strategically positioned in the photoprecursor. Such photochemical cascade fully dearomatizes the benzenoid aromatic ring, saturating all six sp2 atoms to yield a complex sp3-rich scaffold with high control of its 3D molecular shape, rendering it a robust platform for rapid systematic mapping of underexplored chemical space. Significant growth of molecular complexity-starting with a modular synthesis of photoprecursors from readily available building blocks-is quantified by Böttcher score calculations.

Modular Synthesis of Polycarbonyl Compounds via Regioselective Hydration of Oxo-Alkynes.

A novel protocol has been developed for the modular synthesis of polycarbonyl compounds by catalytic hydration of 1,3-diketone-tethered alkynes. The hydration process exhibits good regioselectivity and high yields at room temperature, avoiding the use of strong acids and noble metals and the requirement for elevated temperatures. Mechanistic insights suggest that the hydration proceeds through a concerted process of alkyne protonation and remote carbonyl participation. This approach provides direct access to tandem heterocycle dyads and triads.